The island has "always been a land to control for those who want to rule the boot," says Marco Angelo Gervasoni, political science professor at LUISS university, in reference to the eurozone's boot-shaped third largest economy.
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While he believes it "an important element" in the national ballot – to be held before May – polling expert Alessandro Amadori warns Sicily "is a laboratory, but not so much for the immediate future as for the medium-long term".
The latest polls have the right leading with 35 percent of the vote, just ahead of M5S's 33 percent, while the centre-left Democratic Party (PD) looks set to lose control of the region with a forecast 15 percent.
Here is a run-down of the race and what is at stake.
Five Star Movement (M5S)
Giancarlo Cancelleri, the Five Star Movement's candidate in Sicily. Photo: Marcello Paternostro/AFP.
A win in Sicily would give M5S its first region, a boost supporters say could propel it all the way to national leadership.
Giancarlo Cancelleri, 42, is running on an anti-corruption ticket and hopes to pocket the votes of the undecided or those who usually abstain. But the movement's refusal to join forces with traditional parties could mean not only that it fails to get the majority needed to govern Sicily, but also nationally.
"It's a complex test. The unknown element is voter turnout. And low voter turnout has rewarded M5S in the past in Sicily," says Amadori, vice president of the Istituto Piepoli pollster.
Go Italy (Forza Italia, FI)
Forza Italia president Silvio Berlusconi. Photo: Andreas Solaro/AFP.
Silvio Berlusconi's centre-right party is backing Nello Musumeci, 62, who is leading the race despite heading a tainted electoral list, including candidates who have had brushes with the law.
Former premier Berlusconi, declared politically dead after a series of scandals and open heart surgery last year, is hoping a Sicily victory will put him back in the centre-right driving seat. Portraying himself as a pro-European moderate, he has told voters he is the only real defence against populism.
Musumeci is being backed by FI's traditional rightist allies the Northern League and Brothers of Italy, a coalition combination which pollsters say would likely triumph at the national elections.
Northern League (LN)
Lega Nord secretary Matteo Salvini. Photo: Gabriel Bouys/AFP.
The anti-immigrant party sees Sicily as a testing ground for expanding its reach beyond Italy's northern regions and into the south.
It hopes a win here will strengthen its bid to pick the right's coalition candidate for the general election.
Democratic Party (PD)
Matteo Renzi, secretary of the Democratic Party. Photo: Emmanuel Dunand/AFP.
Battered in the polls, the PD appears to have given up all hope of holding on to Sicily with its candidate Fabrizio Micari, 54.
Political experts say former premier Matteo Renzi is likely to pay the price, with the party accusing the 42-year-old – who hopes to return to power in the spring – of causing a debilitating rift in the left.
The worst-case scenario would see it beaten by Article 1 (MDP), formed in early 2017 by a left-wing split from the PD. Its candidate Claudio Fava, 60, is projected to come in just two percentage points behind the PD's Micari.
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